ProjectNutri-CARE: Nutrient restriction during Critical illness: from induction of Autophagy to Repression of aberrant Epigenetic alterations

Researcher (PI)Greta Herman A Van Den Berghe

Host Institution (HI)KATHOLIEKE UNIVERSITEIT LEUVEN

Call DetailsAdvanced Grant (AdG), LS7, ERC-2012-ADG_20120314

SummaryModern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don’t remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced “reprogramming” and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.

Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don’t remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced “reprogramming” and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.

SummaryLife expectancies in the EU have increased significantly over the past decades and are expected to continue increasing. Age-specific health statuses have also generally been improving. In contrast to these profound changes, the concepts that demographers have used to analyze ageing on a population level have remained largely static. The substantial changes in life expectancy and health status have rendered these traditional demographic measures inadequate for the analysis of ageing at the population level in the 21st century. A better understanding of age and ageing, for both science and policy, requires new approaches. This project will comprehensively reassess population ageing based on innovative alternative definitions of age and ageing as pioneered by the PI.
The project will develop new approaches to the study of age and ageing that are appropriate for 21st century conditions. It will produce new scientific knowledge that is useful in policy formulation and that can educate the public about population ageing and its consequences. Among other things, the proposed project will ascertain the extent to which advanced societies are actually ageing in multiple dimensions, including health, cognitive abilities, and longevity. By addressing such fundamental issues this project will likely have a pronounced impact on future population ageing research.
The new tools and measures developed in the project will facilitate evaluation of the impacts of future changes in public policies, such as increases in statutory pension ages. Applications will be primarily to the EU, but also selected countries experiencing rapid population ageing will be included. The results will be of utmost socioeconomic and political importance for the necessary future restructuring of European pension and health systems in the context of maintaining Europe’s global competitiveness.

Life expectancies in the EU have increased significantly over the past decades and are expected to continue increasing. Age-specific health statuses have also generally been improving. In contrast to these profound changes, the concepts that demographers have used to analyze ageing on a population level have remained largely static. The substantial changes in life expectancy and health status have rendered these traditional demographic measures inadequate for the analysis of ageing at the population level in the 21st century. A better understanding of age and ageing, for both science and policy, requires new approaches. This project will comprehensively reassess population ageing based on innovative alternative definitions of age and ageing as pioneered by the PI.
The project will develop new approaches to the study of age and ageing that are appropriate for 21st century conditions. It will produce new scientific knowledge that is useful in policy formulation and that can educate the public about population ageing and its consequences. Among other things, the proposed project will ascertain the extent to which advanced societies are actually ageing in multiple dimensions, including health, cognitive abilities, and longevity. By addressing such fundamental issues this project will likely have a pronounced impact on future population ageing research.
The new tools and measures developed in the project will facilitate evaluation of the impacts of future changes in public policies, such as increases in statutory pension ages. Applications will be primarily to the EU, but also selected countries experiencing rapid population ageing will be included. The results will be of utmost socioeconomic and political importance for the necessary future restructuring of European pension and health systems in the context of maintaining Europe’s global competitiveness.